Snuff composition

ABSTRACT

Use of a nicotine-cellulose combination for the preparation of a snuff composition for achievement of a fast onset of action of nicotine after application of the snuff composition to the oral cavity of a subject, wherein the composition has a high release rate so that when subjected to an in vitro dissolution test about 45% or more of the total content of nicotine is released within 30 minutes. Moreover, the invention relates to an improved snuff composition for application to the oral cavity.

FIELD OF THE INVENTION

The present invention relates to the use of a nicotine-cellulosecombination for the preparation of a snuff composition for achievementof a fast onset of action of nicotine after application of the snuffcomposition to the oral cavity of a subject, wherein the composition hasa high release rate so that when subjected to an in vitro dissolutiontest about 45% or more of the total content of nicotine is releasedwithin 30 minutes. Moreover, the invention relates to an improved snuffcomposition for application to the oral cavity.

BACKGROUND OF THE INVENTION

Wet snuff is a variant of nicotine addition mainly seen in the US andScandinavia and particularly in Sweden, where this variant is used on adaily basis by approximately 20% of men.

Although wet snuff is not implicated in the cardiovascular and lungdisease morbidity and mortality caused by smoking, the content ofnitrosamines poses a potential hazard for some cancer diseases. It istherefore of interest to make available to consumers a snuff-likeproduct while minimising this potential hazard.

The vascular area at the administration route and the fact that thesnuff is fixed over a long period of time gives an opportunity for botha quick and thorough uptake of nicotine over the mucosa. To develop anew medicated snuff bag ― Snuff Similar ― with similar nicotine effectsbut without the carcinogenic risks derived from the tobacco was theobjective for this project. To reach other countries in Europe andworldwide, one approach would be to have a product that is more cleanand more socially acceptable in its appearance. By using the whitecellulose complex this could be achieved. A more socially acceptablealternative might also potentially increase usage, especially amongwomen

Due to the slow wetting and thereby release, migration and absorption ofnicotine, nicotine release from snuff bags is incomplete in vivo. Apresent snuff variant on the market is “General white” (Swedish Match AB), has a loaded amount of 8.0 mg nicotine per snuff bag and anapproximate in vitro release of 1.4 mg over a period of 30 minutes. Therelease in vivo is consequently less than 20 %. This is mainly due tothe low amount of saliva available to dissolve the nicotine and to thefact that the snuff bag is kept in place over the time ofadministration. Accordingly, in order to load as little nicotine aspossible, there is a need for snuff bag compositions, which have ahigher total release of nicotine. This will also imply that lessnicotine is used in the method for preparation of such snuffcompositions, which is also beneficial from an economic and anenvironmental point of view.

The foregoing has outlined rather broadly the features and technicaladvantages of the present invention in order that the detaileddescription of the invention that follows may be better understood.Additional features and advantages of the invention will be describedhereinafter which form the subject of the claims of the invention. Itshould be appreciated by those skilled in the art that the conceptionand specific embodiment disclosed may be readily utilized as a basis formodifying or designing other structures for carrying out the samepurposes of the present invention. It should also be realized by thoseskilled in the art that such equivalent constructions do not depart fromthe spirit and scope of the invention as set forth in the appendedclaims. The novel features which are believed to be characteristic ofthe invention, both as to its organization and method of operation,together with further objects and advantages will be better understoodfrom the following description when considered in connection with theaccompanying figures. It is to be expressly understood, however, thateach of the figures is provided for the purpose of illustration anddescription only and is not intended as a definition of the limits ofthe present invention.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to the use of a nicotine-cellulosecombination for the preparation of a snuff composition for achievementof a fast onset of action of nicotine after application of the snuffcomposition to the oral cavity of a subject. The composition has a highrelease rate so that when subjected to an in vitro dissolution testabout 45% or more of the total content of nicotine is released within 30minutes.

In general the onset of the nicotine effect is within 5 minutes such as,e.g. within 4 minutes, within 3 minutes, within 2 minutes or within 1.5minutes after application of composition between the lip and the teethof a subject.

In the present context the term “nicotine-cellulose combination” isintended to denote a solid material composed of a cellulose which hassorbed (adsorbed and/or absorbed) a well-defined amount of nicotine(either as free base or as a pharmaceutically acceptable salt, complexor solvate) e.g. in voids or pores within the cellulose. The terms“nicotine-cellulose adduct” and “nicotine-cellulose carrier complex” asused herein are intended to have the same meaning as the term“nicotine-cellulose combination”. As used herein cellulose is an exampleof a carrier.

In WO 2004/056363 (to the same Applicant) is described such anicotine-cellulose combination for release of nicotine. However, thereis no disclosure of the use of such a material for the preparation of asnuff composition for use in the oral cavity.

Moreover, the present inventors have found that the use of such anicotine-cellulose combination is especially suitable for use in a snuffcomposition as such a snuff composition, on the one hand releasesnicotine relatively fast and thereby enables a fast onset of thenicotine effect, and on the other hand enables the nicotine content inthe snuff composition to be completely or almost completely releasedafter application in the oral cavity. The complete or almost completerelease is also seen after encapsulating of the snuff composition in asuitable bag, pouch or membrane. The bag or pouch may be of any suitablematerial e.g. wowen or non-wowen fabric (e.g. cotton, fleece etc.), heatsealable non-wowen cellulose or other polymeric materials such as asynthetic, semi-synthetic or natural polymeric material as describedherein. A material suitable for use must provide a semi-permeablemembrane layer to prevent the powder or composition from leaving the bagor pouch during use. Suitable materials are also those that do not havea significant impact on the release of nicotine from the composition. Tothe best of the inventor’s knowledge, the nicotine/tobacco snuffproducts available on the market today only releases a part of thenicotine contained in the snuff product (see the Examples herein).

The snuff is normally in the form of a bag or pouch suitable for buccaladministration (e.g. to be inserted between the lip and the teeth) andthe bag or pouch comprises the nicotine in the form of anicotine-cellulose combination. In a particular interesting embodiment,the cellulose is microcrystalline cellulose having a mean particle sizeof about 180 µm. An example of a suitable quality is e.g. Avicel PH-200.

The snuff composition according to the present invention may alsocomprise one or more pharmaceutically acceptable excipients or additivesthat are suitable for buccal administration. Such agents include ― butare not limited to ― fillers, binders, wetting agents, stabilizingagents, coloring agents, surface active agents, pH adjusting agents,absorption enhancers, taste-masking agents, flavoring agents,texture-improving agents, etc.

As indicated above, in a specific embodiment of the present invention,the nicotine-cellulose combination (normally together with one or morepharmaceutically acceptable excipients or additives) is enclosed in amembrane material. The membrane may be a natural, synthetic,semi-synthetic hydrophilic or hydrophobic membrane. It may be made fromone or more biocompatible and physiologically acceptable polymericmaterial. Examples of suitable membrane materials are cellulose acetateand derivatives thereof, carboxymethyl cellulose, polycellulose ester,other cellulose derivatives including ethylcellulose, propylcellulose,polyethylene, polypropylene, polystyrene, polyvinyl chloride, polyvinylacetate, polymers of methacrylates and acrylates, natural rubber,polycarbonate, polyethylene terephthalate, polyester, polyamide andnylon. Other suitable materials are mentioned herein before.

In keeping with long-standing patent law convention, the words “a” and“an” when used in the present specification in concert with the wordcomprising, including the claims, denote “one or more.” As used herein“another” may mean at least a second or more. Some embodiments of theinvention may consist of or consist essentially of one or more elements,method steps, and/or methods of the invention. It is contemplated thatany method or composition described herein can be implemented withrespect to any other method or composition described herein.

In one aspect, the invention relates to a snuff composition for buccaladministration in the cheek pouch between the cheek and the jaw or underthe lip. The composition may include tobacco.

The use of tobacco is deeply rooted in a large part of the worldpopulation. In the Scandinavian countries and in particular Sweden theuse of moist snuff (snus) is very common as an alternative to smoking.Snuff is fermented and milled/grinded tobacco with a relatively largewater content (40 - 60 % w/w), normally to be used under the front upperlip of a human being.

Tobacco itself varies somewhat in nicotine content due to its naturalorigin. To adjust the nicotine release in moist snuff, various buffersystems may be added, e.g. carbonates. The moist snuff is either packedloosely, as bulk in a box or as single doses in small non-woven bags. Anumber of the filled and sealed bags are then packed in a box.

The moist snuff as a single dose has become popular due to the ease ofuse compared to the bulk product. The popularity of moist snuff is mostprobably due to its pharmacological nicotine absorption profile. Thedose of nicotine and speed of absorption is approximately 10 ng per mlover 10 minutes though this may vary between brands. Measurements ofplasma nicotine concentrations after a single day of moist snuffconsumption also yielded levels similar to cigarette use. The kineticsare slightly slower compared to the kinetics when smoking tobacco, suchas e.g. cigarettes and cigars; however, the overall amount of nicotineabsorbed is higher when snuff is employed.

A snuff composition according to the invention comprises nicotine, or apharmaceutically acceptable salt, solvate, complex, adduct, orderivative thereof, wherein ― and when subjected to an in vitrodissolution test as described herein for 30 minutes about 30% or more ofthe total content of nicotine is released. This requirement with respectto in vitro release ensures that a sufficient amount of nicotine israpidly available for absorption through the oral mucosa. In particularembodiments, about 35% or more such as, e.g., about 40% or more, about42% or more, about 45% or more, about 50% or more of the total contentof nicotine is released. In embodiments of particular interest, therelease of nicotine is about 45% or more of the total content ofnicotine within 30 minutes (in an in vitro test). Notably, the releasewithin this period of time is about 50% or more such as, e.g., about 60%or more, about 70% or more or about 75% or more of the total content ofnicotine in the snuff composition. The same applies to snuffcompositions encapsulated in a polymeric membrane as described herein.

One important feature of the present invention is that the snuffcomposition leads to a rapid appearance of nicotine in the plasma.Accordingly, in general the in vivo uptake of nicotine 30 minutes afterbuccal administration corresponds to at least about 30% of the totalcontent of nicotine in the snuff. As seen from the examples herein thesnuff composition can be formulated so that the in vivo release ofnicotine 30 minutes after buccal administration is higher, i.e. itcorresponds to at least about 35% such as, e.g., at least about 40%, atleast about 42%, at least about 45%, at least about 50%, at least about55%, at least about 60%, at least about 65%, at least about 70% or atleast about 75% of the total content of nicotine in the snuff.

In a specific embodiment a snuff composition according to the inventioncomprises a carrier comprising internal voids. Such voids may at leastpartially comprise said nicotine. The carrier is typically insoluble inwater or has a low solubility in water. Thus, it typically has asolubility in water at room temperature of less than 1% w/w.

A particular suitable carrier for use in a snuff composition of theinvention is a cellulose, such as a microcrystalline cellulose (“mcc”).The cellulose may be synthetic or semi-synthetic celluloses, or it maybe derived from natural celluloses. It is normally crystalline such asmicrocrystalline. Certain specific embodiments may also utilize otherforms of carriers, in addition to or including mcc, such as but notlimited to fibrous material or carbohydrates including cellulose(including hemicellulose, celluloses with different crystallinities andstructures (e.g., varying structures including solid fibers, andaddition or including fibers or the like in various structures such asweb-like structures and/or other structures), including naturallyoccurring celluloses including Cladophora sp. Algae cellulose or thelike), dextran, agarose, agar, pectin, alginate, xanthan, chitosan,starch (including potato starch, shoti starch) etc. or mixtures thereof.While not intended to be bound by theory, it is believed as of the timeof this patent application that nicotine may interact the carrier (forexample, mcc or other suitable carrier including other cellulosecarriers) by absorbing into and/or adsorbing onto the carrier. Suchinteraction is completely or nearly completely reversible.

The microcrystalline cellulose may be selected from the group consistingof AVICEL® grades PH-100, PH-102, PH-103, PH-105, PH-112, PH-113,PH-200, PH-300, PH-302, VIVACELⓇ grades 101, 102, 12, 20 and EMOCEL®grades 50 M and 90 M, and the like, and mixtures thereof.

Suitable carriers may also be those disclosed in WO 2004/064811, whichis hereby included by reference.

More specifically, it is contemplated that a relatively high surfacearea may be of importance for a carrier that is suitable for use.Accordingly, the specific surface area of suitable carriers is normallyat least 0.7 m²/g such as, e.g., 1 m²/g. In certain uses the specificsurface area may range between about 0.7 m²/g and at least about 100m²/g and/or may be anything within this range and/or may be any mixtureof sizes within this range. For example, in certain embodiments, thesurface area may be about 0.7 m²/g, about 1 m²/g, about 1.5 m²/g, about2.0 m²/g, about 3.0 m²/g, about 5 m²/g, about 7 m²/g, about 10 m²/g,about 15 m²/g, about 20 m²/g, about 25 m²/g, about 35 m²/g, about 45m²/g, about 50 m²/g, about 75 m²/g, about 100 m²/g and above about 100m²/g, or combinations thereof. Such carriers having such suitablesurface areas may include, but are not limited to, mcc, fibrous materialor carbohydrates including cellulose (including hemicellulose,celluloses with different crystallinities and structures (e.g., varyingstructures including solid fibers, and addition or including fibers orthe like in various structures such as web-like structures and/or otherstructures), including naturally occurring celluloses includingCladophora sp. Algae cellulose or the like), dextran, agarose, agar,pectin, alginate, xanthan, chitosan, starch (including potato starch,shoti starch) etc. and/or mixtures thereof.

In a specific embodiment, nicotine is sorbed on microcrystallinecellulose.

In general, the mean particle size of the carrier such asmicrocrystalline cellulose is one that is not too low and neither toohigh such as, e.g., at the most about 500 µm, at the most about 450 µm,at the most about 300 µm, or at the most about 200 µm, or from about 5to about 500 µm, from 10 to about 500 µm, from 15 to about 500 µm, fromabout 20 to about 500 µm, from about 30 to about 500 µm, from about 40to about 500 µm, from about 10 to about 400 µm, from about 20 to about400 µm, from about 30 to about 400 µm, from about 40 to about 400 µm,from about 30 to about 300 µm, from about 40 to about 300 µm, from about50 to about 250 µm, from about 50 to about 200 µm or from about 75 toabout 200 µm. In specific embodiments the particle size used were about100 µm. In a preferred aspect, the mean particle size is in a range offrom about 15 to about 250 µm such as from about 20 to about 200 µm. Inthe examples herein a quality of microcrystalline cellulose having amean particle size of 180 µm has proved to be well-suited for thepresent purpose.

In a preferred embodiment a snuff composition according to the inventioncontains nicotine as a nicotine-microcrystalline cellulose carriercomplex in which said nicotine is at least partly sorbed onmicrocrystalline cellulose and/or is at least partially absorbed intothe carrier and/or is at least partially adsorbed onto the carrier(e.g., mcc), or mixtures thereof. Such interaction is completely ornearly completely reversible

Hence, in certain specific embodiments nicotine is sorbed onmicrocrystalline cellulose, absorbed into the mcc and/or adsorbed ontothe mcc, and/or combinations thereof.

In embodiments of the present invention, the carrier (e.g., but notlimited to mcc and/or other naturally-occurring cellulose) is at leastpartially porous. This porosity may be due, for example but not limitedto, the structure of the carrier, for example, branched, fibrous, orweblike structures may have pores. Ranges of pore sizes include but arenot limited to pore volumes of about 0.01 cm³/g and include, but are notnecessarily limited to pore volume ranges of from about 0.003 cm³/g orless to about 0.025 cm³/g, to about or greater than 0.60 cm³/g.

In general, the nicotine carrier complex or nicotine carrier adduct ispresent in a snuff composition of the invention in a concentration of atleast about 2% w/w such as in a range from about 2% w/w to about 98%w/w, from about 2% to about 96% w/w, from about 2% w/w to about 95% w/w,from about 3 % w/w to about 90% w/w, from about 4 % w/w to about 85%w/w, from about 5 % w/w to about 80% w/w, from about 5 % w/w to about75% w/w, from about 5 % w/w to about 70% w/w, or from about 7.5% w/w toabout 65% w/w.

In certain embodiments, the amount of nicotine sorbed, for exampleabsorbed into and/or adsorbed onto to carrier can be up to 50% or moreof the total weight of the composition. Ranges of the amount of nicotinesorbed onto the carrier in the present invention range for less thanabout 1% of the total weight of the composition to more than about 50%of the composition, including all amounts within this range. Whileapplicants do not intend the invention to be bound by theory, it isbelieved at the time of preparing this application that the maximumamount of nicotine that can be sorbed onto and/or into the carrier,thereby affecting the amount, for example the percent nicotine by weightof the total composition (e.g., the maximum percentage) is affected byproperties of the carrier, including but not limited to the structure ofthe carrier, the porosity of the carrier, and the surface area of thecarrier.

In certain embodiments, the concentration of the nicotine carriercomplex or nicotine carrier adduct in a composition of the invention ispresent in a concentration such as, e.g., from about 80% w/w to about98% w/w, such as, e.g., from about 85% w/w to about 98% w/w, from about90% w/w to about 98% w/w, from about 92% w/w to about 98% w/w, fromabout 93% w/w to about 97% w/w or from about 94% w/w to about 96% w/w.

In an alternative embodiment, the carrier compound is capable of forminga complex with nicotine such as, e.g., in the case that the carriercompound is an ion-exchange compound including polacrilex.

Concentrations and Amounts of Nicotine

As mentioned above, nicotine may be present in any suitable form.Normally, nicotine is selected from the group consisting of nicotinebase, nicotine hydrochloride, nicotine dihydrochloride, nicotinemonotartrate, nicotine bitartrate, nicotine sulfate, nicotine zincchloride such as nicotine zinc chloride monohydrate and nicotinesalicylate. In a preferred aspect, nicotine is in its free base form,which easily can be sorbed on a cellulose to form a microcrystallinecellulose-nicotine carrier complex or carrier adduct.

Normally, the nicotine compound (calculated as the free base) is presentin a concentration of at least about 0.1% w/w such as in a range fromabout 0.1% w/w to about 50% w/w such as, e.g., from about 0.5% w/w toabout 45% w/w, from about 1.0% w/w to about 40% w/w, from about 1.5% w/wto about 35% w/w, from about 2% w/w to about 30% w/w, from about 2.5 %w/w to about 25% w/w, from about 2.5 % w/w to about 20% w/w, from about3% w/w to about 15% w/w.

However, in a more interesting embodiment a snuff composition accordingto the invention contains nicotine in a concentration from about 0.1%w/w to about 10% w/w, such as, e.g., from about from about 0.1% w/w toabout 8% w/w, from about 0.1% w/w to about 6% w/w, from about 0.1% w/wto about 4% w/w, from about 0.1% w/w to about 2% w/w, from about 0.1%w/w to about 1.5% w/w, from about 0.2% w/w to about 1.0% w/w or fromabout 0.2% w/w to about 0.8% w/w, calculated as free base.

In a snuff composition of the invention the nicotine is typicallypresent in a concentration from about 0.1% w/w to about 5% w/w, such as,e.g., from about from about 0.1% w/w to about 4% w/w, from about 0.1%w/w to about 3% w/w, from about 0.1% w/w to about 2% w/w, from about0.1% w/w to about 1% w/w, from about 0.1% w/w to about 0.75% w/w, fromabout 0.2% w/w to about 0.5% w/w or from about 0.2% w/w to about 0.4%w/w, calculated as free base.

As mentioned above, the nicotine is present in the form of anicotine-cellulose combination. In general, this combination is presentin a concentration of from about 5% to about 100% such as, e.g., fromabout 10 to about 100%, from about 5% to about 50% or, alternatively,from about 45% to about 100%. The choice of suitable concentrationdepends on the load of nicotine in the nicotine-cellulose combinationand the dosage of nicotine in a single pouch or bag. If the load isrelatively high, then the concentration of the combination may be lowerthan if the load is relatively low. In a specific embodiment using e.g.Avicel® or a similar cellulose quality a concentration of thecombination is generally from about 80% w/w to about 98% w/w, such as,e.g., from about 85% w/w to about 98% w/w, from about 90% w/w to about98% w/w, from about 92% w/w to about 98% w/w, from about 93% w/w toabout 97% w/w or from about 94% w/w to about 96% w/w.

The concentration of nicotine (or the pharmaceutically acceptable salt,complex or solvate thereof) in the combination is at the most 70% w/wsuch as, e.g., at the most 60% w/w, at the most 50% w/w, at the most 45%w/w. The content of nicotine must not be so high that the combination(which is in powder form) “sweats”, so that nicotine desorbs, evaporatesor otherwise disappears from the combination. Accordingly, the load ofnicotine in the combination is dependent on the particular celluloseemployed. If the surface area of the cellulose material is relativelyhigh, then a larger amount of nicotine can be contained therein in astable manner during a suitable period of time, whereas a cellulosehaving a smaller surface area normally is indicative for a lowercapacity to load nicotine in a suitable manner with respect tostability.

For most cellulose qualities, the concentration of nicotine in thenicotine-cellulose combination is at the most about 45% w/w, such as,e.g., at the most about 40% w/w, at the most about 35% w/w, at the mostabout 30% w/w, at the most about 25% w/w, at the most about 20% w/w, atthe most about 15% w/w, at the most about 12.5% w/w, at the most about10% w/w, at the most about 9.5% w/w, at the most about 9% w/w, at themost about 8.5% w/w or at the most about 8% w/w, and the concentrationbeing calculated as the nicotine base.

In a specific embodiment, a particulate material according to thepresent invention has a concentration of nicotine or thepharmaceutically acceptable salt, complex or solvate thereof in theparticulate material is at the most about 7.5% w/w such as, e.g., at themost about 7% w/w, at the most about 6.5 % w/w, at the most about 6%w/w, at the most about 5.5% w/w, at the most about 5% w/w, at the mostabout 4.5% w/w, at the most about 4% w/w, at the most about 3% w/w, atthe most about 2% w/w or at the most about 1% w/w, and the concentrationbeing calculated as the nicotine base.

The amount of the nicotine compound (calculated as the free base) in acomposition of the inventions is generally from about 0.5 mg to about 10mg such as, e.g., from about 1 mg to about 8 mg, from about 1.5 mg toabout 7.5 mg, from about 2 mg to about 5 mg, from about 2.5 mg to about5 mg, from about 3 to about 10 mg, from about 3 to about 7.5 mg or fromabout 3 mg to about 5 mg such as, e.g., about 1.5 mg, about 2 mg, about2.5 mg, about 3 mg, about 3.5 mg, about 4 mg, about 5 mg or about 6 mg,as calculated as free nicotine base. In particular a dosage of 2 mg, 3mg, 4 mg and 6 mg is of commercial interest.

Buffering Agents

A composition according to the invention may also contain one or morebuffering agents. It is generally known that a slightly alkalinereaction (between 7 and 8) in the oral cavity enhances the absorption ofnicotine. Accordingly, it may be and advantage to incorporate a buffersubstance in the composition such that a slightly alkaline reaction isprovided. Especially compositions for release of the nicotine in theoral cavity can advantageously contain a buffer substance, i.e.compositions like snuff compositions.

Suitable buffering agents are typically those selected from the groupconsisting of acetates, glycinates, phosphates, glycerophosphates,citrates such as citrates of alkaline metals, carbonates, and hydrogencarbonates, and borates, or mixtures thereof. Especially, a carbonate, ahydrogen carbonate or a phosphate including a triphosphate is suitableas a buffer agent.

If present the one or more buffering agents are present in aconcentration from about 0.5% w/w to about 5% w/w, such as, e.g., fromabout 0.75% w/w to about 4%, w/w, from about 0.75% w/w to about 3%, w/wor from about 1% w/w to about 2%, w/w.

In a specific embodiment, the concentration of the one or more bufferingagents is from about 0.1% w/w to about 5% w/w, such as, e.g., from about0.2% w/w to about 4% w/w, from about 0.3% w/w to about 4% w/w, fromabout 0.4% w/w to about 3% w/w, from about 0.5% w/w to about 2% w/w,from about 0.6% w/w to about 1% w/w or from about 0.7% w/w to about 0.9%w/w such as about 0.8% w/w.

Sweeteners ― Flavouring Agents

In order to improve the sensory properties of the composition accordingto the invention one or more sweeteners or texture improves may beadded, such as sugar alcohols including xylitol, sorbitol, maltitoland/or isomalt, or artificial sweeteners such as e.g. aspartame,acesulfame or saccharin.

The concentration of the one or more sweeteners, if present, is normallyat least about 0.05% such as, e.g. from about 0.075% w/w to about 5% w/wor from about 5% to about 35% w/w, such as, e.g., from about 10% w/w toabout 35% w/w, from about 15% w/w to about 35% w/w or from about 20% w/wto about 30% w/w. In an interesting embodiment the one or moresweeteners are present in a concentration from about 0.01% w/w to about0.2% w/w, such as, e.g., from about 0.01 % w/w to about 0.15% w/w, fromabout 0.02% w/w to about 0.12% w/w, from about 0.03% w/w to about 0.11%w/w, from about 0.04% w/w to about 0.1% w/w, from about 0.05% w/w toabout 0.1% w/w, from about 0.06% w/w to about 0.1% w/w or from about0.07% w/w to about 0.09% w/w such as about 0.08% w/w. As demonstrated inthe examples herein a concentration of the one or more artificialsweeteners of about 0.08% gives good sensoric acceptance.

In order to improve the organoleptic properties of a compositionaccording to the invention, the composition may include one or moreflavouring agents, such as, e.g., menthol flavour, eucalyptus, mintflavour and/or L-menthol, normally present (total concentration offlavouring agents) in a concentration of from about 0.5% w/w to about12% w/w, from about 1% w/w to about 10% w/w, from about 1.5% w/w toabout 9% w/w or from about 2% w/w to about 8% w/w.

In a particular embodiment the flavour is mint flavour and theconcentration of the one or more flavouring agents is from about 1% w/wto about 15% w/w, such as, e.g., from about 1% w/w to about 10% w/w,from about 1.5% w/w to about 8% w/w, from about 2% w/w to about 6% w/wor from about 3% w/w to about 5% w/w such as about 4% w/w. In a specificembodiment, the concentration of the one or more flavouring agents isabout 4% w/w.

It is well-known that nicotine is subject to oxidation and accordingly,it may be advantageous to incorporate one or more anti-oxidants, suchas, e.g., ascorbyl palmitate and/or sodium ascorbate, in a compositionaccording to the invention.

The one or more anti-oxidants may be present in a concentration of fromabout 0.4% w/w to about 2.4% w/w, such as, e.g., from about 0.5% w/w toabout 2.2% w/w, from about 0.6% w/w to about 2% w/w, from about 0.7% w/wto about 1.8% w/w or from about 0.8% w/w to about 1.6% w/w.

Specific Embodiments

In specific embodiments the invention relates to

-   A snuff composition comprising    -   i) a carrier,    -   ii) nicotine, or a pharmaceutically acceptable salt, solvate,        complex, or derivative thereof, wherein at least about 30% w/w        of the total content of nicotine is released within 30 minutes        when said composition is subjected to an in vitro dissolution        test.-   A snuff composition comprising    -   i) a nicotine-cellulose combination    -   ii) one or more pharmaceutically acceptable excipients or        additive the composition being encapsulated in a bag, pouch or        membrane material.-   A snuff composition comprising    -   i) a nicotine-cellulose combination containing from about 0.5 to        about 10 mg of nicotine    -   ii) a flavoring agent    -   iii) a sweetener the composition being encapsulated in a bag,        pouch or membrane material.-   A snuff composition comprising    -   i) a nicotine-cellulose combination containing from about 0.5 to        about 10 mg of nicotine    -   ii) a flavoring agent    -   iii) a sweetener    -   iv) an antioxidant the composition being encapsulated in a bag,        pouch or membrane material.

A method of administering a snuff composition with a high release ratecomprising the step of: delivering a snuff composition comprising acarrier combined with nicotine, or a pharmaceutically acceptable salt,solvate, complex, or derivative thereof, wherein at least about 30% w/wof the total content of nicotine is released within 30 minutes when saidcomposition is subjected to an in vitro dissolution test.

A method of making a snuff composition with a high release rate,comprising the step of: combining nicotine, or a pharmaceuticallyacceptable salt, solvate, complex, or derivative thereof, with acarrier, wherein at least about 30% w/w of the total content of nicotineis released within 30 minutes when said composition is subjected to anin vitro dissolution test.

All particulars and details mentioned above relating to the main aspectin general apply mutatis mutandis to the above mentioned specificembodiments.

The invention is further illustrated in the followingfigures andnon-limiting examples.

Legends to the Figures

FIG. 1 shows an assembly of the dialysis membrane to the silicone hose -the assembly is a part of the dissolution testing apparatus for testingof snuff compositions

FIG. 2 shows an overview of tubing routes in the dissolution testing ofsnuff compositions

FIG. 3 shows a sample tube for dissolution testing of snuff compositions

FIGS. 4 and 5 show in vitro release profile for snuff compositionsdescribed in Example 2

FIGS. 6 and 7 show the in vivo uptake of nicotine from snuffcompositions described in Example 3.

FIG. 8 show the plasma concentration versus time for the experimentdescribed in Example 5 comparing NicoretteⓇ chewing gum (4 mg) with asnuff composition of the invention containing 5 mg of nicotine

METHODS In Vitro Dissolution Test

The snuff compositions according to the invention are normally tested tofulfill specific requirements with respect to in vitro release ofnicotine. A suitable in vitro test depends on the specific compositionin question. In general, a person skilled in the art will find guidanceas to how to choose a relevant dissolution test for a specificcomposition in the official monographs such as, e.g., the EuropeanPharmacopoeia. Below are described suitable dissolution tests in case ofsnuff compositions.

Snuff

The following dissolution method for testing of the release of nicotinefrom snuff compositions was used.

The method describes in-vitro release of nicotine from snuff using UVdetection. The released nicotine diffuses through a dialysis membraneinto a stream of tempered phosphate buffer.

Equipment

-   UV spectrophotometer HP 8453 or equivalent-   Sipper HP Peristaltic pump or equivalent-   Secondary pump Flexicon PF5 or equivalent-   Magnetic stirrer Labasco or equivalent-   Water bath Gant W14 or equivalent

Instrument settings

-   UV spectrophotometer Wavelengths 244.259 and 274 nm Flow cell 1.000    cm-   Waterbath Temperature 37° C.-   Secondary pump Pump flow 30 rpm-   Magnetic stirrer Rotation Gentle stir

Materials

-   Dialysis membrane, Spectra/Por®, MWCO 500,-   Silicon tubing, i.d. 6 mm-   Sample tube-   250 ml beaker

Reagents

-   Chemicals & solvents:-   Purified water, H₂O-   Sodium Hydroxide, min 98%, NaOH-   Sodium Dihydrogen Phosphate Monohydrat, min 98%, NaH₂PO₄ · H₂O

Reference material:

-   Nicotine bitartrate dihydrate, standard

Solutions:

-   5 M Sodium hydroxide-   Phosphate buffer, pH 6.8

Procedure

Apparatus assembly

Cut two pieces of silicon hoses, 150 and 35 cm long. Insert a 3 cm longhard plastic hose (o.d. 7 mm) in one end of the two ‘blood vessels’ forsupport. Cut a piece of dialysis membrane and pre-treat according tomanufacturer. Thread the membrane through two 2.5 cm long silcon hosepieces (i.d. 6 mm). The supported ends of the blood vessels should beinserted approximately 3 cm into the membrane and secured with the twosmall silicon rings (See FIG. 1 ).

Add 250 ml phosphate buffer [6] to the 250 ml beaker and add a magneticbar. Place it in the water bath and start the heating and rotation.Connect the silicone hose to the secondary pump and place the longestpart to the beaker. Place a pipette tip (1 ml) into the shorter end towork as a pressure restrictor. The hole in the tip may be expanded inorder to adjust the back pressure. Prime the tubing with buffer.

Place the two tubings from the flow cell in the beaker. (See FIG. 2 )and obtain a blank measurement.

Stop the flow and fold the membrane on the middle. Use a piece of paperto slide the membrane into the sample tube as far down as possible.Start the pump and carefully insert the snuff bag halfway down thesample tube between the membranes (see FIG. 3 ). Add phosphate buffer[2] to the tube enough to cover the sample. Place the sample tube in thewater bath and start the analysis.

Sampling

Blank: Measure blank before the membrane is placed into the sample tube.

Sampling: Withdraw sample online every fifth minute for 30 minutes usingthe sipper. Measure the absorbance at 244, 259 and 274 nm.

Standards: Pump S1-S3 into the flow cell after the sampling sequence.Measure the absorbance at 244, 259 and 274 nm.

Evaluation

The concentrations of nicotine in the samples are calculated.

As an alternative method, USP basket method (in vitro dissolution oftablets) can be used employing 500 ml water as dissolution medium.

The following examples are included to demonstrate preferred embodimentsof the invention. It should be appreciated by those of skill in the artthat the techniques disclosed in the examples that follow representtechniques discovered by the inventor to function well in the practiceof the invention, and thus can be considered to constitute preferredmodes for its practice. However, those of skill in the art should, inlight of the present disclosure, appreciate that many changes can bemade in the specific embodiments which are disclosed and still obtain alike or similar result without departing from the spirit and scope ofthe invention.

EXAMPLES Example 1 Snuff Bag Compositions E, F, G, H, I and J

Nicotine was sorbed onto microcrystalline cellulose (MCC) as describedin WO 2004/056363. Accordingly, in the present example 2.40 ml nicotinewas dissolved in 25 ml ethanol (99.5%). 47.6 g MCC of type PH-102 wasloaded into a high-speed mixer and the nicotine was slowly added. Aftervacuum drying of the obtained wetted mass a fine-grained, white powderof nicotine-microcrystalline cellulose carrier complex was obtained.

Nicotine was sorbed onto microcrystalline cellulose (MCC) to obtainnicotine-microcrystalline cellulose carrier complexes essentially asdescribed above. The obtained nicotine-microcrystalline cellulosecarrier complexes were mixed with the remaining ingredients to obtainthe compositions E, F, G, H, I and J stated in the following table:

COMPO-SITION Compo-sition E Compo-sition F Compo-sition G Compo-sition HCompo-sition I Compo-sition J Ingredient Quantity (mg/unit) Quantity(mg/unit) Quantity (mg/unit) Quantity (mg/unit) Quantity (mg/unit)Quantity (mg/unit) Nicotine 6.00 6.00 6.00 4.00 4.00 6.00Microcry-stalline cellulose 138 137 137 139 139 135 Pepper-mint powderflavour 6.00 6.00 6.00 6.00 6.00 6.00 Acesul-fame potassium 0.06 0.060.06 0.06 0.06 0.06 Asparta-me powder 0.06 0.06 0.06 0.06 0.06 0.06Sodium carbonate — — — — — 1.20 Sodium hydrogen carbonate — 1.20 — 1.20— 1.20 Sodium triphos-phate — — 1.20 — 1.20 — Target Weight 150 150 150150 150 150 Measured pH, 5 g in 100 ml H2O 9.47 9.02 10.4-10.8 8.9510.3-10.5 9.95 In-vitro release, 30 min (mg)* 2.6 2.6 2.6-2.7 1.81.6-1.7 3.0 Measured assay 5.9 6.0 6.0-6.3 4.2 3.8-4.2 6.3

Nicotine was purchased from Siegfried, Switzerland, (batch no.0338l006), Microcrystalline cellulose was purchased from FMC, Belgium(batch no. M301C), Peppermint powder flavour was purchased fromFirmenich, Switzerland (batch no. JP05040527), Acesulfame potassium waspurchased from L&P Food Ingredient, China (batch no. (ZD02035),Aspartame powder was purchased from NutraSweet, Switzerland (batch no.C000220), Sodium carbonate was purchased from Aldrich, Germany (batchno. A008729Pl), Sodium hydrogen carbonate was purchased from Merck,Germany (batch no. K28409723047), Sodium triphosphate was purchased fromSigma, USA (supplied from Swedish Match Sweden).

150 mg of the compositions E-J, respectively, were filled into snuffbags made of a snuff bag material obtained from Swedish Match, Sweden(batch no. W-NR00217, RL-NR6). The snuff bag size used is similar to thepresent marketed dry snuff bags, i.e. as “Catch® dry”.

Example 2 In Vitro Release From Snuff Bag Compositions E, F, G, H, I andJ

Measurement of in vitro release rates of nicotine from snuff bags wereperformed using an in vitro dissolution test developed at Swedish Match,Stockholm, and utilizing a plastic flow-chamber in a tube with buffersolution combined with UV detection on a spectrophotometer at 260 nm.The details are mentioned above under the heading “In vitro dissolutiontest”.

The in vitro release of nicotine from compositions E-J in percentage ofthe total content of nicotine are stated in the table below:

COMPO-SITION Compo-sition E Compo-sition F Compo-sition G Compo-sition HCompo-sition I Compo-sition J Nicotine content (mg) 6.00 6.00 6.00 4.004.00 6.00 In vitro release, 30 min (mg) 2.6 2.6 2.6-2.7 1.8 1.6-1.7 3.0Percentage of released nicotine 43% 43% 43-45% 45% 40-42% 50%

Furthermore, comparison studies of the in vitro release profiles ofnicotine from snuff bags containing snuff compositions according to thepresent invention and already marketed snuff bags were performed. InFIG. 4 the in vitro release profiles of nicotine from compositions F andH were compared with the in vitro release profiles of nicotine from thepresent marketed dry snuff bags “Catch® dry” and “general white” usingthe first of the above-mentioned in vitro release methods. FIG. 4illustrates the improved in vitro release of nicotine from snuffcompositions according to the present invention compared to both “Catch®dry” and “general white”: Snuff composition F which contains 6 mgnicotine releases significantly more nicotine than the already marketedproducts “Catch® dry” and “general white”. As the marketed products arenatural products information of the exact content of nicotine is notavailable, but it is disclosed that the weight is 1 gram or less, thenicotine content is 5-11 mg, the pH is 7.3-8.5 and the buffer content is1.5-3.5%.

In FIG. 5 the in vitro release rates of nicotine from snuff compositionsE, F and G containing 6 mg of nicotine and snuff compositions H and Icontaining 4 mg of nicotine, were compared to the in vitro release ratesof nicotine from “General” compositions 1, 2 and 3. Again, the snuffcompositions according to the present invention exhibit a better releaserelative to the total content of nicotine in the composition/product.

Example 3 In Vivo Uptake of Nicotine From Snuff Bag ContainingComposition

A comparison study of the in vivo uptake of nicotine from the snuffproduct “General”, 4 mg NicoretteⓇ chewing gum and a snuff bagcomprising composition J was performed. Composition J contained 0.8%sodium hydrogen carbonate and 0.8% sodium carbonate. Blood samples weretaken at 0, 5, 10, 15, 20, 30 and 40 minutes after application and theplasma concentrations of nicotine were determined by ABS laboratories,London, England. After addition of sodium hydroxide, the plasma sampleswere extracted with dichloroethane and nicotine was quantitativelydetermined by gas chromatography using a nitrogen/phosphorous detector.5-methyl cotinine was used to internally standardize the procedure. Thelimit of quantification is 0.5 ng/ml.

The results are shown in FIG. 6 . For comparison reasons the in vivouptake of nicotine from the snuff product “General” was normalized to anicotine content of 6 mg. FIG. 6 shows that over a time period of 30minutes, the snuff bag containing composition J provides a plasma levelof nicotine exceeding those of both “General” and NicoretteⓇ4 mgnicotine chewing gum.

Furthermore, a pilot pharmacokinetic study (n=4) in which the in vivouptake of nicotine from snuff compositions G, J and I were compared tothe in vivo uptake from NicoretteⓇ 4 mg chewing gum. The result shown inFIG. 7 illustrates that the in vivo uptake of nicotine from each ofthese snuff compositions is significantly better than from NicoretteⓇ 4mg chewing gum.

Example 4 Residual Amounts of Nicotine in Snuff Bags Comprising SnuffCompositions G, I And J - In Vitro vs. In Vivo

Snuff bags comprising either of compositions G, I or J were subjected toeither the above-mentioned in vitro dissolution test employing USPbasket apparatus or the above-mentioned pilot pharmacokinetic assay in30 minutes. Subsequently, the residual nicotine content in the snuffbags was investigated using a dissolution bath combined with aUV-detection on a spectrophotometer at 260 nm. The dissolution wasdetermined according to the dissolution method for tablets USP (basket)using 500 ml water as dissolution medium and a temperature of 37° C.

The results are shown in the following table:

Snuff composition Composition I Composition G Composition J Measurednicotine assay (mg) 3.8 6.3 6.3 Mean in vitro residual amount nicotineafter 30 minutes (n=2) (mg) 1.9 3.6 3.3 Mean in vitro residual amountnicotine after 30 minutes (n=2) (%) 50 57 52 Mean in vivo residualamount 1.98 3.06 2.84 nicotine after 30 minutes (n=4) (mg) Mean in vivoresidual amount nicotine after 30 minutes (n=4) (%) 52 49 45 Diversionin vitro vs in vivo (% vs %) - 2 + 8 + 7

It follows from the figures in the above table, that the residual amountof nicotine in the snuff bags after 30 minutes of in vitro dissolutiontest is between 50% and 57% of the initial content of nicotine, i.e.between 43% and 50% of the nicotine has been released in the in vitrodissolution test. It further follows that the residual amount ofnicotine in the snuff bags after 30 minutes of the in vivopharmacokinetic study, is between 45% and 50% of the initial content ofnicotine, i.e. between 45% and 50% of the nicotine has been absorbed inthe bloodstream.

Example 5 Comparison of Nicorette 4 mg Gum with MCC-Nicotine ContainingSnuff Composition with 5 mg Nicotine

Single dose pharmacokinetics was studied in four subjects in comparisonto Nicorette 4 mg gum (FIG. 8 ). FIG. 8 shows the results from a singledose pharmacokinetic study in four subject comparing NicoretteⓇ 4 mgchewing gum with a snuff composition containing MCC-nicotinecorresponding to 5 mg nicotine after oral application.

The bioavailability of nicotine from the nicotine snuff compositionappears higher that that seen for the Nicorette® composition even if thedifferent in dosage is taken into account.

References

All patents and publications mentioned in the specification areindicative of the levels of those skilled in the art to which theinvention pertains. All patents and publications are herein incorporatedby reference to the same extent as if each individual publication wasspecifically and individually indicated to be incorporated by reference.

Although the present invention and its advantages have been described indetail, it should be understood that various changes, substitutions andalterations can be made herein without departing from the spirit andscope of the invention as defined by the appended claims. Moreover, thescope of the present application is not intended to be limited to theparticular embodiments of the process, machine, manufacture, andcomposition of matter, means, methods and steps described in thespecification. As one of ordinary skill in the art will readilyappreciate from the disclosure of the present invention, processes,machines, manufacture, compositions of matter, means, methods, or steps,presently existing or later to be developed that perform substantiallythe same function or achieve substantially the same result as thecorresponding embodiments described herein may be utilized according tothe present invention. Accordingly, the appended claims are intended toinclude within their scope such processes, machines, manufacture,compositions of matter, means, methods, or steps.

1. A snuff composition comprising: (a) about 80% to about 98% by weight,based on the weight of the snuff composition, of a solidnicotine-cellulose combination formed of porous cellulose having thenicotine sorbed into the pores thereof, the nicotine (calculated as freebase) being present at a concentration of about 0.1% to about 10% byweight, based on the weight of the snuff composition; (b) a flavoringagent; and (c) a buffering agent; wherein the composition is enclosed ina bag, pouch, or membrane.
 2. The snuff composition of claim 1, whereinthe nicotine and cellulose are combined such that, when subjected to anin vitro dissolution test using UV detection, about 30% or more of thetotal content of the nicotine is released from the composition within 30minutes. 3-6. (canceled)
 7. The snuff composition of claim 1, whereinthe nicotine and cellulose are combined such that, when subjected to anin vitro dissolution test using UV detection, about 45% or more of thetotal content of the nicotine is released from the composition within 20minutes.
 8. (canceled)
 9. The snuff composition of claim 1, wherein thecomposition comprises about 85% to about 98% by weight of thenicotine-cellulose combination.
 10. (canceled)
 11. The snuff compositionof claim 1, wherein the cellulose is derived from a source selected fromthe group consisting of a plant, an algae, a bacterium, a fungi, andcombinations thereof.
 12. (canceled)
 13. The snuff composition of claim1,wherein the cellulose is microcrystalline cellulose.
 14. (canceled)15. The snuff composition of claim 13, wherein the microcrystallinecellulose is derived from natural cellulose.
 16. The snuff compositionof claim 1, wherein the cellulose has a surface area of at least 0.7m²/g.
 17. The snuff composition of claim 1, wherein the cellulose has amean particle size of about 500 µm or less. 18-20. (canceled)
 21. Thesnuff composition of claim 1, wherein the nicotine is nicotine free baseor a pharmaceutically acceptable salt, solvate, complex, or derivativethereof. 22-24. (canceled)
 25. The snuff composition of claim 1, whereincomposition comprises about 1% to about 15% by weight, based on theweight of the snuff composition, of the flavoring agent.
 26. The snuffcomposition of claim 25, wherein the composition comprises about 1.5% toabout 8% by weight of the flavoring agent.
 27. The snuff composition ofclaim 1, wherein the composition comprises about 0.1% to about 5% byweight, based on the weight of the snuff composition, of the bufferingagent.
 28. The snuff composition of claim 27, wherein the compositioncomprises about 0.5% to about 2% by weight of the buffering agent.29-34. (canceled)
 35. The snuff composition of claim 1, wherein thecomposition is enclosed in the bag or pouch, and wherein the bag orpouch is a woven material, a non-woven material, or a polymericmaterial.
 36. The snuff composition of claim 1, further comprising asweetener.
 37. The snuff composition of claim 36, wherein thecomposition comprises about 0.01% to about 0.2% by weight, based on theweight of the snuff composition, of the sweetener.
 38. The snuffcomposition of claim 1, further comprising an antioxidant.
 39. The snuffcomposition of claim 38, wherein the composition comprises about 0.4% toabout 2.4% by weight, based on the weight of the snuff composition, ofthe antioxidant.
 40. (canceled)